It has long been known that almost all pharmacologically active compounds are most effective when present in the blood plasma within a certain concentration range. Above this range, there sometimes may be a danger of deleterious side effects. Also, excess drug in the blood plasma may be wasted if the concentration is significantly above the blood level that results in the maximum pharmacological effect, thus making both the manufacture and use of the drug formulation unnecessarily costly. Alternatively, when the concentration of drug in the plasma is below the most effective range, there is the danger that the active ingredient may not be maximally effective, or may not be effective at all.
When physiologically possible, an oral dosage form is the preferred route of administration of most pharmaceutical compounds because it provides easy, low cost administration. However, patient compliance is an important factor to consider in conjunction with oral administration of a pharmaceutical compound, especially if the compound must be taken three or four times a day. To maximize patient compliance, it is desirable to reduce the number of daily dosage units a patient must take to attain effective therapy. The use of fewer, longer acting dosages also improves the constancy of drug concentrations in the blood over time, and since the drug can be closer to its ideal therapeutic dosage throughout the day, this may result in improved therapy.
Nifedipine (3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester) is a calcium channel antagonist which has been successfully used in the treatment of coronary artery spasms and hypertension. The administration of nifedipine in traditional capsule or tablet form requires the patient to remember to ingest tablets or capsules several times per day in order to maintain effective blood levels of the drug. In addition, many patients being treated on this drug regimen must take several other capsules or tablets for the treatment of other conditions or disease states, requiring a large total number of pills to be taken daily. Moreover, the administration of the drug several times per day results in non-constant blood levels throughout the day. Accordingly, it is important for the convenience of the patient, and to ensure dosage compliance, that the frequency of administration of nifedipine be kept to a minimum. It is also important that the level of nifedipine maintained in the blood plasma of a patient be relatively constant within the effective dosage range for the entire dosage period.
One method of accomplishing these goals is the use of controlled release formulations, some of which are well known in the prior art. Some controlled release formulations are comprised of a solid polymeric matrix throughout which a pharmaceutical compound has been dispersed. After the formulation is ingested, the active pharmaceutical compound slowly releases from the polymer matrix, resulting in prolonged release of the active ingredient.
Another method for achieving controlled release of a pharmaceutical agent relies on an osmotic pressure mechanism. European patent No. 0 386 440 A1, issued to Bayer AG, discloses nifedipine tablets having various specified surface areas in a controlled release, once daily formulation of nifedipine. The formulation releases nifedipine via an osmotic release mechanism; the diffusion of water into the tablet through a semi-permeable membrane causes pressure to build inside the tablet, which forces the drug out through a pinhole in the tablet coating. A controlled release tablet that releases nifedipine in this way is commercially available from Pfizer, Inc. under the trade name Procardia XL.RTM., and this tablet has been found to give generally acceptable drug release profiles in vivo.
European Patent No. 0 5145683, issued to Ethical Pharmaceuticals, Inc., discloses a controlled release pharmaceutical composition comprising particles of a water-soluble material coated with microcrystalline particles of nifedipine and polyvinylpyrrolidone, the latter of which is present in an amount of from 10 to 90% by weight based on the weight of the nifedipine. The incorporation of polyvinylpyrrolidone in an amount less than that of the nifedipine is said to significantly slow the dissolution of nifedipine from the final dosage form.
Another approach to formulating controlled release compositions includes the dry blending of one or more polymer with the desired drug, forming a composition which, when exposed to fluid, forms a gel; the drug is then slowly released by diffusion from the gel.
Yet another approach to controlled release is the coating of small pellets (e.g., sugar beads or nonpareils) with the drug, followed by a coating with a barrier layer of some polymer which impedes the release of the drug into the liquid of the digestive system. Such small beads are often then packaged together to provide an oral dosage form, e.g., by placing the beads into a gelatin capsule.
The methods and formulations of the present invention use this latter approach, which heretofore has not successfully been applied to the controlled release delivery of nifedipine. The formulations of the present invention provide controlled release formulations in the form of pellets having multiple layers coated thereon, which provide for controlled release of the pharmaceutical agent from the individual pellets. The pellets may be then formulated into controlled release tablets or capsules. The controlled release of nifedipine from pellets prepared by the process of this invention maintains a constant blood level of nifedipine over a prolonged period of time. By using the methods of the present invention, it has been possible to prepare controlled release nifedipine formulations that have essentially the same in vitro drug release profiles (drug release as a function of time) as does Procardia XL.RTM..